14.2 - Metabolic + Endocrine Control During Special Circumstances

Question 1

What are the main fuel sources normally available in the blood

Answer 1

glucose
- Preferred fuel source
- Little free glucose available, most stored as glycogen
- Some cells have an absolute requirement for glucose (different card)
fatty acids
- Can be used as fuel by most cells
- Stored as triacylglycerol (fat) in adipose tissue
- 10-15kg fat in 70kg man
- Roughly 2 months energy store
- Generate energy (ATP) using β oxidation

Question 2

What cells have an absolute requirement for glucose

Answer 2

• Some lymphocytes
• Kidney medulla
• Cells of cornea
• Red blood cells (have no mitochondria)
• Brain (can gradually adjust to using ketone bodies)
• CNS
  These cells rely on glycolysis and glucose is their only energy source

Question 3

What are the fuel sources available under special conditions

Answer 3

amino acids
- Breakdown of skeletal muscle
- Converted to glucose or ketone bodies
- Roughly 2 weeks supply of energy
ketone bodies
- Mainly from fatty acids
- Used when glucose is critically short
- Glucose sparing effect (where glucose is saved for the cells that have obligate requirement eg CNS)
- Brain can gradually adjust to metabolising this instead of glucose
lactate
- Product of anaerobic metabolism in muscle
- When oxygen runs out, muscle produces lactate from pyruvate
- Lactate can be recycled in liver by being converted back to glucose (Cori cycle)
- Or can be used as a fuel source for TCA cycle in other tissues eg in heart

Question 4

What are the main energy stores in the body

Answer 4

glycogen
- Readily available source of glucose
- Made and stored in liver + muscle
- Made when excess glucose in blood
fat
- Made from glucose + dietary fats when in excess
- Stored as triacylglycerol in adipose tissue
- Source of fatty acid + glycerol
muscle protein
- Used in emergency
- Amino acids can be glucogenic and/or ketogenic
- Store is ‘filled’ by normal growth and repair processes
note: Ketogenic amino acids form acetoacetate or acetyl CoA. Glucogenic amino acids form pyruvate, α-ketoglutarate, succinyl CoA, fumarate, or oxaloacetate

Question 5

Key features of metabolic control

Answer 5

after feeding, glucose and fat are available from gut
- Immediate metabolism supported by glucose
- Increase rate of growth and repair processes
- Make glycogen rapidly + increase fat stores
after eating, glucose and fats no longer being absorbed
- Maintain blood glucose by using glycogen stores
- Support other metabolic activity with fatty acids from stores
- Preserve blood glucose for brain
after glycogen stores depleted
- Gluconeogenesis from AAs, glycerol and lactate
- Continue to support other metabolism with fatty acids
prolonged starvation
- Fatty acid metabolism produces ketone bodies
- Brain adjusts to be able to metabolise ketone bodies
- This reduces brain’s need for glucose

Question 6

Catabolic + anabolic hormones for metabolic control

Answer 6

anabolic hormones
- Promote fuel storage
- Eg insulin – a lack of this → catabolic state
- Growth hormone (inc protein synthesis + gluconeogenesis)
catabolic hormones
- Promote release + use of energy stores
- Eg thyroid hormones, adrenaline + cortisol (promote increase in BMR)
- Eg glucagon
- Eg growth hormone (increases lipolysis + glycogenolysis)

Question 7

Effects of insulin (basic)

Answer 7

stops
- Gluconeogenesis
- Lipolysis
- Proteolysis
- Ketogenesis
- Glycogenolysis
go
- Glycolysis
- Glycogen synthesis
- Protein synthesis
- Promoting translocation of GLUT4 which allows tissues to take up glucose from meal to utilise in glycolysis or store (by muscle and adipose)

Question 8

Effects of feeding

Answer 8

• Increase in blood glucose stimulates β cells in pancreas to release insulin
• Increases glucose uptake by GLUT4 and utilisation by muscle or adipose
• Promotes storage of glucose as glycogen in liver and muscle
• Promotes amino acid uptake + protein synthesis in liver and muscle
• Promotes lipogenesis and storage of fatty acids as triacylglycerols in adipose tissue

Question 9

Effects of fasting

Answer 9

• Blood glucose falls
• Insulin secretion depressed
• Reduces uptake of glucose by adipose and muscle
• Low blood glucose stimulates glucagon from α cells
• Glucagon stimulates
  ☞ glycogenolysis in liver to maintain blood glucose for glucose dependent tissues
  ☞ lipolysis in adipose tissue to provide fatty acids for use by tissues
  ☞ gluconeogenesis to maintain supplies of glucose for dependent tissues

Question 10

Energy starvation

Answer 10

• Reduction of blood glucose → stimulates release of cortisol (from adrenal cortex) and glucagon (α pancreas)
• Stimulate gluconeogenesis, proteolysis + lipolysis for energy
• Insulin effects reduced, preventing cells from using glucose
• Fatty acids are preferentially metabolised
• Glycerol from fat is substrate for gluconeogenesis, reducing need for proteolysis
• Glucose sparing effect: Liver produces ketone bodies → brain starts to use these
• Kidneys begin to contribute to gluconeogenesis
• Once fat stores depleted, protein sources used as fuel
• Death usually related to loss of muscle mass (eg diaphragm and therefore breathing compromised)

Question 11

What is a mother’s net weight gain by end of pregnancy

Answer 11

• roughly 8kg
• This consists of foetus, placenta, amniotic fluid and maternal fuel stores
• Require most energy during final trimester as this is when most foetal growth occurs

Question 12

Two main phases of metabolic adaptation during pregnancy

Answer 12

anabolic phase
- Early pregnancy
- Preparatory increase in maternal nutrient stores (particularly adipose)
- This is because need energy stores for rapid growth (third trimester) and preparation for lactation
- Small increase in insulin sensitivity so that fat can take up more glucose
catabolic phase
- Later pregnancy
- Maternal metabolism adapts to meet an increasing demand by fetal-placental unit
- Decreased insulin sensitivity (increased insulin resistance)
- This promotes availability of glucose for foetus
- Increase in insulin resistance results in an increase in maternal glucose + fatty acid concentration so that there is greater availability for foetus

Question 13

How do substances get across placenta

Answer 13

• Most by simple diffusion down concentration gradient
• Some active transport eg amino acid transporters
  glucose
  ☞ prinicipal fuel for foetus
  ☞ transfer across placenta facilitated by GLUT1 transporter
  ☞ GLUT1 is concentration-dependent (not insulin dependent)

Question 14

What is fetoplacental unit

Answer 14

• Foetus controls maternal metabolism to ensure its own survival
• Aka ‘aggressive parasite’
• New endocrine entity (fetoplacental unit) = placenta, fetal adrenal glands and fetal liver
• Wide range of hormones/proteins produced by placenta that can control the maternal hypothalamic pituitary axis
• Eg CRH, GnRH, TRH, GHRH (hypothalamic like releasing hormones) and ACTH, hCG, cCT, hPL (pituitary like hormones)
• Some steroid hormones also produced eg oestriol + progesterone

Question 15

Maternal metabolic changes during first half of pregnancy

Answer 15

increased insulin : anti-insulin ratio
- Related to preparatory increase in maternal nutrient stores
- This is mainly increase in adipose tissues
- In preparation for rapid growth of foetus, lactation and birth
- increasing levels of insulin (therefore increased insulin : anti-insulin ratio)
- anti-insulin hormones = cortisol + adrenaline etc
- this promotes an anabolic state in mother that results in increased nutrient storage

Question 16

maternal metabolic changes during second half of pregnancy

Answer 16

decreased insulin : anti-insulin ratio
- maternal metabolism adapts to meet increasing demands of foetus
- concentration of nutrients in the maternal circulation kept relatively high due to…
☞ glucose sparing: reduce maternal use of glucose by switching tissues to use fatty acid
☞ delay maternal disposal of nutrients after meals → better transfer of glucose to foetus
☞ release fatty acids from stores
- maternal insulin levels continue to increase
- however, production of anti-insulin hormones (by fetoplacental unit) increases at even faster rate
- therefore insulin : anti-insulin rate falls

Question 17

why can pregnancy result in hyperglycaemia

Answer 17

• placenta secretes several hormones that exert an anti-insulin effect on maternal metabolism
• can result in transient hyperglycaemia due to increased insulin resistance
• insulin levels are still increased during pregnancy, but there are greater amounts of anti-insulin hormones

Question 18

why can hypoglycaemia occur in pregnancy (between meals and at night)

Answer 18

foetus is continually drawing glucose from mother

Question 19

insulin secretion in pregnancy

Answer 19

• increased appetite during pregnancy
• means more glucose ingested
• oestrogen + progesterone increase sensitivity of maternal β pancreas cells to glucose… this is done by β cell hypertrophy + hyperplasia
• this increases insulin synthesis and secretion
• if β cells don’t respond normally, blood glucose can become very elevated → can develop gestational diabetes
• more about this on next cards

Question 20

what is gestational diabetes and the 3 known underlying causes

Answer 20

disease in which pancreatic β cells do not provide sufficient insulin to meet increased requirement in late pregnancy
☞ affects 3-10% of pregnancies
- β cell dysfunction in setting of obesity + insulin resistance (evolving T2 DM, predisposed to T2). Most common.
- Autoantibodies similar to those characteristically in T1 DM. Rarer.
- Genetic susceptibility similar to maturity onset diabetes. Rare.

Question 21

Complications of gestational diabetes

Answer 21

• Increased incidence of miscarriage
• More likely to have congential malformation
• Fetal macrosomia (big baby) → childbirth problems related to baby size
• Extra adipose tissue around shoulders and chest → shoulder dystocia (shoulders get stuck)
• Hypertension: preeclampsia + gestational hypertension risk
  The risk of complications is reduced if diagnosed + managed

Question 22

How does starting point of insulin resistance before pregnancy affect risk of developing gestational diabetes?

Answer 22

• Naturally, insulin resistance increases with age
• This is due to having more fat and less lean body mass
• If start with low insulin resistance before pregnancy, pregnancy will be unlikely to cause diabetes threshold to be reached
• If start with higher insulin resistance (high risk woman) before pregnancy, pregnancy will cause increased insulin resistance
• This could reach diabetes threshold, causing gestational diabetes
• Will revert back to pre-diabetic state after preganancy
• However, the presence of gestational diabetes suggests that woman is more likely to develop T2 DM later in life

Question 23

Risk factors for gestational diabetes

Answer 23

• Maternal age over 25 (more likely to reach diabetic threshold of insulin resistance during pregnancy, as insulin resistance already increases with age)
• BMI of over 25 kg/m2
• More common in Asian, black and hispanic ethnic groups
• Personal or family history of diabetes
• Family history of macrosomia (big baby)

Question 24

What is the management of gestational diabetes

Answer 24

• Initial dietary modification, inc calorie reduction in obesity
• Insulin injection if persistent hyperglycaemia present
• Regular monitoring to reduce risk of complications
• This includes regular ultrasound scans to assess fetal growth

Question 25

Metabolic response to exercise

Answer 25

• Very rapid switch from resting to exercise state
• Need to provide energy to meet increasing deman
• Involves adaptations in resp, cardio, msk + temperature regulation systems
• Minimal disturbances to metabolism homeostatis by keeping energy mobilisation equal to rate of utilisation
• Need to ensure enough glucose for dependent tissues
• Need to ensure products are removed as quickly as possible eg acid
• Response depends on type of exercise (muscles used), intensity, duration of exercise, physical state and nutrition of individual

Question 26

Energy requirements of exercise

Answer 26

• ATP → ADP + Pi + energy
• Need this for power stroke for sliding filament theory to facilitiate muscle contraction
• Also need for other cellular processes eg maintaining ionic gradients across the cell membrane
• ATP stores in muscle are very limited
• ATP must be rapidly resynthesised at a rate that meets metabolic cell demands
• Cell will employ different metabolic strategies to match resynthesis with rate of hydrolysis
• Can use creatine phosphate stores to rapidly replenish ATP (from ADP) to provide immediate energy. However this is very short-lived but provides enough time fo glycolysis to kick in
• Beyond initial burst of energy, further ATP must be supplied by glycolysis + oxidative phosphorylation (so need to draw on energy stores)

Question 27

How is muscle glycogen used during exercise

Answer 27

☞ Anaerobic breakdown of glycogen (producing lactate) can sustain some intense exercise
☞ If exercise is low intensity enough, O2 can be supplied for complete oxidation of glucose + glycogen stores (from muscle and liver)

• glycogenolysis by muscle glycogen phosphorylase. This is increased by adrenaline + AMP. Produces Glucose 6 Phosphate which is used in glycolysis
• Glycolysis is regulated by phosphofructokinase, which is stimulated by high AMP and inhibited by high ATP.
• Pyruvate is produced, and can enter TCA cycle in aerobic conditions, and lactate is end product under anaerobic conditions
• Lactate can be recycled by Cori cycle, taken to liver and converted to glucose again, which is fed back to muscle.

Question 28

What is the Cori Cycle

Answer 28

• The liver recycles the lactate produced by anaerobic metabolism
• Lactate produced anaerobically by muscle is transported to liver by bloodstream
• Liver converts 2 lactate into glucose
• Glucose is transported to muscle where it can be used in respiration

Question 29

What is the prinicipal organ for regulating blood glucose

Answer 29

• The liver
• Exercise results in an increase in hepatic blood glucose production through glycogenolysis and gluconeogenesis
• Liver recycles lactate produced from anaerobic metabolism (Cori Cycle, card above)

Question 30

How does muscle take up blood glucose

Answer 30

• Predominantly via GLUT4 (insulin promotes translocation to plasma membrane)
• Also via GLUT1 (constituitevly active, meaning it’s insulin independent)
• Exercising muscle also has insulin independent process of glucose uptake…
  ☞ increase in AMP → stimulates AMPK → signalling cascade → promotes GLUT4 translocation → more glucose uptake into cells
• Rate of glucose production from liver is insufficient to meet full demands of exercising muscle

Question 31

Fatty acids as fuel

Answer 31

• Triacylglycerol is mainly stored in adipose, but also some in muscle itself
• Can only be used in aerobic conditions
• Slow release from adipose tissue
• Not easily transported in blood – limited carrying capacity
• Capacity limited by uptake across mitochondrial membrane (carnitine shuttle)
• Low rate of ATP production
• High capacity for sustained production

Question 32

Short, high intensity exercise

Answer 32

• Eg 100m sprint
• Cannot deliver enough O2 to muscles in time
• Once high energy phosphate stores used, must revert to anaerobic respiration
• This creates ATP inefficiently due to incomplete metabolism of glucose (this is going to lactate, not TCA cycle)
• The lactate produced → build up of H+
• This causes fatigue + cramps
• Need muscle store of glycogen: has glucose sparing effect so that glucose is saved for glucose-dependent tissues

Question 33

Middle distance exercise, medium intensity

Answer 33

• Eg 1500m
• Can deliver some extra O2 but significant part still anaerobic
• Aerobic can use fatty acid metabolism as well as glucose
• Initial start uses creatine phosphate and anaerobic glycogen metabolism
• Long middle phase relies on O2 delivery to tissues → ATP produced aerobically
• Finishing sprint relies again on anaerobic metabolism of glycogen…produces lactate

Question 34

Long distance + long duration exercise

Answer 34

• Eg marathon
• Low intensity but long
• Mainly aerobic respiration
• Use of muscle + liver glycogen, and fatty acid metabolism
• Muscle glycogen is depleted quickly
• Liver glycogen is used and then depletes
• Fatty acid utilisation

Question 35

Hormonal control of the metabolic response to prolonged exercise

Answer 35

Eg in marathon
* insulin falls slowly due to adrenaline production. Adrenaline inhibits insulin
* glucagon rises:
☞ activates glycogen phosphorylase (stimulating glycogenolysis)
☞ activates PEPCK + fructose 1,6 bisphosphatase (stimulating gluconeogenesis)
☞ activates hormone sensitive lipase (stimulating lipolysis – release of fatty acids)
* adrenaline increases rapidly, stimulating glycogenolysis + lipolysis
* growth hormone increases rapidly to stimulate gluconeogenesis + lipolysis
* cortisol rises slowly, increasing lipolysis + gluconeogenesis

Question 36

Benefits of exercise

Answer 36

• Body composition: decrease adipose, increase muscle
• Glucose tolerance improves
• Increased insulin sensitivity
• Decrease in VLDL + LDL, increase HDL
• Decrease in blood pressure
• Good psychological effects
• Reverses progression of metabolic disease
• Can improve T2 DM dramatically